1,361
Views
5
CrossRef citations to date
0
Altmetric
REVIEW

Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

ORCID Icon & ORCID Icon
Pages 261-277 | Received 12 Jul 2022, Accepted 06 Feb 2023, Published online: 06 Apr 2023

References

  • Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. Am J Hematol. 2020;95(6):691–709. doi:10.1002/ajh.25792
  • Nicholson E, Holyoake T. The chronic myeloid leukemia stem cell. Clin Lymphoma Myeloma. 2009;9(Suppl 4):S376–381. doi:10.3816/CLM.2009.s.037
  • Frazer R, Irvine AE, McMullin MF. Chronic myeloid leukaemia in the 21st century. Ulster Med J. 2007;76(1):8–17.
  • García-Gutiérrez V, Hernández-Boluda JC. Tyrosine kinase inhibitors available for chronic myeloid leukemia: efficacy and safety. Front Oncol. 2019;9. doi:10.3389/fonc.2019.00603
  • Sasaki K, Strom SS, O’Brien S, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2(5):e186–193. doi:10.1016/S2352-3026(15)00048-4
  • Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917–927. doi:10.1056/NEJMoa1609324
  • Etienne G, Guilhot J, Rea D, et al. Long-term follow-up of the French stop imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol off J Am Soc Clin Oncol. 2017;35(3):298–305. doi:10.1200/JCO.2016.68.2914
  • Oka S, Muroi K, Mori M, et al. Prediction of response to imatinib in patients with chronic myelogenous leukemia by flow cytometric analysis of bone marrow blastic cell phenotypes. Leuk Lymphoma. 2009;50(2):290–293. doi:10.1080/10428190802627598
  • Kang ZJ, Liu YF, Xu LZ, et al. The Philadelphia chromosome in leukemogenesis. Chin J Cancer. 2022;35:48. doi:10.1186/s40880-016-0108-0
  • Holmberg M. Is the primary event in radiation-induced chronic myelogenous leukemia the induction of the t(9;22) translocation? Leuk Res. 1992;16(4):333–336. doi:10.1016/0145-2126(92)90134-S
  • Ismail SI, Naffa RG, Yousef AMF, Ghanim MT. Incidence of bcr‑abl fusion transcripts in healthy individuals. Mol Med Rep. 2014;9(4):1271–1276. doi:10.3892/mmr.2014.1951
  • Aplan PD. Causes of oncogenic chromosomal translocation. Trends Genet TIG. 2006;22(1):46–55. doi:10.1016/j.tig.2005.10.002
  • Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood. 2022;113(8):1619–1630. doi:10.1182/blood-2008-03-144790
  • Verma D, Kantarjian HM, Jones D, et al. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009;114(11):2232–2235. doi:10.1182/blood-2009-02-204693
  • Arun AK, Senthamizhselvi A, Mani S, et al. Frequency of rare BCR-ABL1 fusion transcripts in chronic myeloid leukemia patients. Int J Lab Hematol. 2017;39(3):235–242. doi:10.1111/ijlh.12616
  • Cortes JE, Talpaz M, Beran M, et al. Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer. 1995;75(2):464–470. doi:10.1002/1097-0142(19950115)75:2<464::AID-CNCR2820750209>3.0.CO;2-E
  • Seong D, Kantarjian HM, Albitar M, et al. Analysis of Philadelphia chromosome-negative BCR-ABL-positive chronic myelogenous leukemia by hypermetaphase fluorescence in situ hybridization. Ann Oncol off J Eur Soc Med Oncol. 1999;10(8):955–959. doi:10.1023/A:1008349405763
  • Onida F, Ball G, Kantarjian HM, et al. Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer. 2002;95(8):1673–1684. doi:10.1002/cncr.10832
  • Ohyashiki JH, Ohyashiki K, Ito H, Toyama K. Molecular and clinical investigations in Philadelphia chromosome-negative chronic myelogenous leukemia. Cancer Genet Cytogenet. 1988;33(1):119–126. doi:10.1016/0165-4608(88)90057-X
  • Wang SA, Hasserjian RP, Fox PS, et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood. 2014;123(17):2645–2651. doi:10.1182/blood-2014-02-553800
  • Diamantopoulos PT, Viniou NA. Atypical chronic myelogenous leukemia, BCR-ABL1 negative: diagnostic criteria and treatment approaches. Front Oncol. 2021;11:722507. doi:10.3389/fonc.2021.722507
  • Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254–2264. doi:10.1172/JCI41246
  • Yohannan B, George B. B-lymphoid blast phase–chronic myeloid leukemia: current therapeutics. Int J Mol Sci. 2022;23(19):11836. doi:10.3390/ijms231911836
  • Nowicki MO, Falinski R, Koptyra M, et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. Blood. 2004;104(12):3746–3753. doi:10.1182/blood-2004-05-1941
  • Koptyra M, Falinski R, Nowicki MO, et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood. 2006;108(1):319–327. doi:10.1182/blood-2005-07-2815
  • Skorski T. Oncogenic tyrosine kinases and the DNA-damage response. Nat Rev Cancer. 2002;2(5):351–360. doi:10.1038/nrc799
  • Chereda B, Melo JV. Natural course and biology of CML. Ann Hematol. 2015;94(Suppl 2):107–121. doi:10.1007/s00277-015-2325-z
  • Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood.2009;113(8):1619–1630. doi:10.1182/blood-2008-03-144790
  • How HR. I treat CML blast crisis. Blood. 2012;120(4):737–747. doi:10.1182/blood-2012-03-380147
  • Adnan Awad S, Dufva O, Ianevski A, et al. RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses. Leukemia. 2021;35(4):1087–1099. doi:10.1038/s41375-020-01011-5
  • Ochi Y, Yoshida K, Huang YJ, et al. Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia. Nat Commun. 2021;12(1):2833. doi:10.1038/s41467-021-23097-w
  • Soliman DS, Amer AM, Mudawi D, et al. Chronic myeloid leukemia with cryptic Philadelphia translocation and extramedullary B-lymphoid blast phase as an initial presentation. Acta Bio. 2018;89(3–S):38–44.
  • Zagaria A, Anelli L, Albano F, et al. A fluorescence in situ hybridization study of complex t(9;22) in two chronic myelocytic leukemia cases with a masked Philadelphia chromosome. Cancer Genet Cytogenet. 2004;150(1):81–85. doi:10.1016/j.cancergencyto.2003.08.018
  • Alhuraiji A, Kantarjian H, Boddu P, et al. Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol. 2018;93(1):84–90. doi:10.1002/ajh.24943
  • Krishna Chandran R, Geetha N, Sakthivel KM, Suresh Kumar R, Jagathnath Krishna KMN, Sreedharan H. Impact of additional chromosomal aberrations on the disease progression of chronic myelogenous leukemia. Front Oncol. 2019;5(9):88. doi:10.3389/fonc.2019.00088
  • Chen Z, Shao C, Wang W, et al. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2017;31(3):585–592. doi:10.1038/leu.2016.231
  • Clark RE, Apperley JF, Copland M, Cicconi S. Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression. Blood Adv. 2021;5(4):1102–1109. doi:10.1182/bloodadvances.2020003570
  • Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–984. doi:10.1038/s41375-020-0776-2
  • Meggyesi N, Kozma A, Halm G, Nahajevszky S, Bátai A, Fekete S, et al. Additional chromosome abnormalities, BCR-ABL tyrosine kinase domain mutations and clinical outcome in Hungarian tyrosine kinase inhibitor-resistant chronic myelogenous leukemia patients. Acta Haematol. 2012;127(1):34–42.
  • Siti Mariam I, Norhidayah R, Zulaikha AB, et al. Differential prognostic impact of stratified additional chromosome abnormalities on disease progression among Malaysian chronic myeloid leukemia patients undergoing treatment with imatinib mesylate. Front Oncol. 2022;12. doi:10.3389/fonc.2022.720845
  • Houshmand M, Simonetti G, Circosta P, et al. Chronic myeloid leukemia stem cells. Leukemia. 2019;33(7):1543–1556. doi:10.1038/s41375-019-0490-0
  • Jiang X, Zhao Y, Smith C, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia. 2007;21(5):926–935. doi:10.1038/sj.leu.2404609
  • Kavalerchik E, Goff D, Jamieson CHM. Chronic myeloid leukemia stem cells. J Clin Oncol off J Am Soc Clin Oncol. 2008;26(17):2911–2915. doi:10.1200/JCO.2008.17.5745
  • Herrmann H, Cerny-Reiterer S, Gleixner KV, et al. CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin. Haematologica. 2012;97(2):219–226. doi:10.3324/haematol.2010.035006
  • Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells – what challenges do they pose? Nat Rev Drug Discov. 2014;13(7):497–512. doi:10.1038/nrd4253
  • Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol. 1993;11:245–268. doi:10.1146/annurev.iy.11.040193.001333
  • Sadovnik I, Herrmann H, Eisenwort G, et al. Expression of CD25 on leukemic stem cells in BCR-ABL1+ CML: potential diagnostic value and functional implications. Exp Hematol. 2022;51:17–24. doi:10.1016/j.exphem.2017.04.003
  • Herrmann H, Sadovnik I, Cerny-Reiterer S, et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014;123(25):3951–3962. doi:10.1182/blood-2013-10-536078
  • Gschwandtner M, Paulitschke V, Mildner M, et al. Proteome analysis identifies L1CAM/CD171 and DPP4/CD26 as novel markers of human skin mast cells. Allergy. 2017;72(1):85–97. doi:10.1111/all.12919
  • Ali S, Huber M, Kollewe C, Bischoff SC, Falk W, Martin MU. IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. Proc Natl Acad Sci U S A. 2007;104(47):18660–18665. doi:10.1073/pnas.0705939104
  • Kinstrie R, Horne GA, Morrison H, et al. CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy. Leukemia. 2020;34(6):1613–1625. doi:10.1038/s41375-019-0684-5
  • Chu S, McDonald T, Lin A, et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood. 2022;118(20):5565–5572. doi:10.1182/blood-2010-12-327437
  • Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776–779. doi:10.1038/nature07737
  • Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet. 2009;41(7):783–792. doi:10.1038/ng.389
  • Kuepper MK, Bütow M, Herrmann O, et al. Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling. Leukemia. 2019;33(8):1964–1977. doi:10.1038/s41375-019-0427-7
  • Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood. 2017;129(12):1595–1606. doi:10.1182/blood-2016-09-696013
  • Skorski T. BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma. 2008;49(4):610–614. doi:10.1080/03093640701859089
  • Stoklosa T, Poplawski T, Koptyra M, et al. BCR/ABL inhibits mismatch repair to protect from apoptosis and induce point mutations. Cancer Res. 2008;68(8):2576–2580. doi:10.1158/0008-5472.CAN-07-6858
  • Cramer K, Nieborowska-Skorska M, Koptyra M, et al. BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair. Cancer Res. 2008;68(17):6884–6888. doi:10.1158/0008-5472.CAN-08-1101
  • Zhang B, Chu S, Agarwal P, et al. Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor-treated CML stem cells. Blood. 2016;128(23):2671–2682. doi:10.1182/blood-2015-11-679928
  • Bhatia R. TARGETING LEUKEMIA STEM CELL RESISTANCE IN CHRONIC MYELOGENOUS LEUKEMIA. Trans Am Clin Climatol Assoc. 2019;130:246–254.
  • Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol OncolJ Hematol Oncol. 2020;13(1):104. doi:10.1186/s13045-020-00937-8
  • Gallipoli P, Cook A, Rhodes S, et al. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood. 2014;124(9):1492–1501. doi:10.1182/blood-2013-12-545640
  • Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2017;1(28):iv41–51. doi:10.1093/annonc/mdx219
  • Deininger MW, Shah NP, Altman JK, et al. Chronic myeloid leukemia, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw JNCCN. 2020;18(10):1385–1415. doi:10.6004/jnccn.2020.0047
  • Asnafi AA, Deris Zayeri Z, Shahrabi S, Zibara K, Vosughi T. Chronic myeloid leukemia with complex karyotypes: prognosis and therapeutic approaches. J Cell Physiol. 2019;234(5):5798–5806. doi:10.1002/jcp.27505
  • ClinicalKey. Chronic myeloid leukemia; 2022. Available from: https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323357623000676?scrollTo=%23hl0000264. Accessed February 10, 2023.
  • Arunachalam AK, Jain M, Kumar A, Kushwaha R, Singh US, Tripathi AK. Megakaryocytes in chronic phase of chronic myeloid leukemia: a descriptive case series. Ann Pathol Lab Med. 2016;3(3):A176–182.
  • Mughal Z, Babar H, Ashraf S, Hamid A, Khokhar A, Qamar S. Megakaryocytic clustering in chronic myeloid leukemia: can it be a predictor of clinical outcome? J Coll Physicians Surg. 2021;31(1):34–38. doi:10.29271/jcpsp.2021.01.34
  • Dekmezian R, Kantarjian HM, Keating MJ, Talpaz M, McCredie KB, Freireich EJ. The relevance of reticulin stain-measured fibrosis at diagnosis in chronic myelogenous leukemia. Cancer. 1987;59(10):1739–1743. doi:10.1002/1097-0142(19870515)59:10<1739::AID-CNCR2820591011>3.0.CO;2-2
  • Haznedaroğlu İC, Kuzu I, Ilhan O. WHO 2016 definition of chronic myeloid leukemia and tyrosine kinase inhibitors. Turk J Hematol. 2020;37(1):42–47.
  • Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405. doi:10.1182/blood-2016-03-643544
  • Ivanov S, Sharma P, Jobanputra Y, Zhang Y. Transformation of chronic myeloid leukemia to acute biphenotypic leukemia. J Med Cases. 2020;11(8):239–242. doi:10.14740/jmc3511
  • Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the world health organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi:10.1182/blood-2016-01-643569
  • Padhi P, Topalovski M, El Behery R, Cantu ES, Medavarapu R, Rare A. Case of chronic myelogenous leukemia presenting as T-cell lymphoblastic crisis. Case Rep Oncol Med. 2018;2018:7276128. doi:10.1155/2018/7276128
  • Andretta E, Costa C, Longobardi C, et al. Potential approaches versus approved or developing chronic myeloid leukemia therapy. Front Oncol. 2022;11:801779. doi:10.3389/fonc.2021.801779
  • Simonsson B, Gedde-Dahl T, Markevärn B, et al. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood. 2011;118(12):3228–3235. doi:10.1182/blood-2011-02-336685
  • Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363(26):2511–2521. doi:10.1056/NEJMoa1004095
  • Gratwohl A, Pfirrmann M, Zander A, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016;30(3):562–569. doi:10.1038/leu.2015.281
  • O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004. doi:10.1056/NEJMoa022457
  • Iqbal N, Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother Res Pract. 2022;2014:357027.
  • Uzer E, Ünal A, Köker MY, Doğan SA. The Side Effects of Imatinib. Turk J Hematol. 2022;30(3):341. doi:10.4274/TJH-2011.0018
  • Mughal TI, Schrieber A. Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. Biol Targets Ther. 2010;2(4):315–323. doi:10.2147/BTT.S5775
  • Prost S, Le Dantec M, Augé S, et al. Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARgamma/STAT5 signaling pathway in macaques. J Clin Invest. 2008;118(5):1765–1775. doi:10.1172/JCI33037
  • Breccia M, Alimena G. Second-Generation Tyrosine Kinase Inhibitors (Tki) as salvage therapy for resistant or intolerant patients to prior TKIs. Mediterr J Hematol Infect Dis. 2014;6(1):e2014003. doi:10.4084/mjhid.2014.003
  • Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol off J Am Soc Clin Oncol. 2016;34(20):2333–2340. doi:10.1200/JCO.2015.64.8899
  • Cortes JE, Jiang Q, Wang J, et al. Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study. Leukemia. 2020;34(8):2064–2073. doi:10.1038/s41375-020-0805-1
  • Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–1054. doi:10.1038/leu.2016.5
  • Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol off J Am Soc Clin Oncol. 2018;36(3):231–237. doi:10.1200/JCO.2017.74.7162
  • Do YR, Kwak JY, Kim JA, et al. Long-term data from a Phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE). Br J Haematol. 2020;189(2):303–312. doi:10.1111/bjh.16381
  • O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–412. doi:10.1016/j.ccr.2009.09.028
  • Zhou T, Commodore L, Huang WS, et al. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des. 2011;77(1):1–11. doi:10.1111/j.1747-0285.2010.01054.x
  • Chan O, Talati C, Isenalumhe L, et al. Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia. Blood Adv. 2020;4(3):530–538. doi:10.1182/bloodadvances.2019000268
  • Alves R, Gonçalves AC, Rutella S, et al. Resistance to tyrosine kinase inhibitors in chronic myeloid leukemia-from molecular mechanisms to clinical relevance. Cancers. 2021;13(19):4820. doi:10.3390/cancers13194820
  • Meenakshi Sundaram DN, Jiang X, Brandwein JM, Valencia-Serna J, Remant KC, Uludağ H. Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. Drug Discov Today. 2019;24(7):1355–1369. doi:10.1016/j.drudis.2019.05.007
  • Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A Phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–1796. doi:10.1056/NEJMoa1306494
  • Galinsky I, Buchanan S. Guide to interpreting disease responses in chronic myeloid leukemia. J Adv Pract Oncol. 2022;3(4):225–236.
  • Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809–1820. doi:10.1182/blood-2006-02-005686
  • Branford S. Why is it critical to achieve a deep molecular response in chronic myeloid leukemia? Haematologica. 2022;105(12):2730–2737. doi:10.3324/haematol.2019.240739
  • Ebian HF, Abdelnabi ASM, Abdelazem AS, Khamis T, Fawzy HM, Hussein S. Peripheral blood CD26 positive leukemic stem cells as a possible diagnostic and prognostic marker in chronic myeloid leukemia. Leuk Res Rep. 2022;17:100321. doi:10.1016/j.lrr.2022.100321
  • Kuntegowdanahalli LC, Kanakasetty GB, Thanky AH, et al. Prognostic and predictive implications of Sokal, Euro and EUTOS scores in chronic myeloid leukaemia in the imatinib era—experience from a tertiary oncology centre in Southern India. Ecancermedicalscience. 2022;10:679.
  • Pfirrmann M, Clark RE, Prejzner W, et al. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia. Leukemia. 2022;34(8).
  • Munje C, Copland M. Exploring stem cell heterogeneity in chronic myeloid leukemia. Trends Cancer. 2022;4(3):167–169. doi:10.1016/j.trecan.2017.12.001
  • Jeanpierre S, Arizkane K, Thongjuea S, et al. The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission. Haematologica. 2022;106(1):111–122. doi:10.3324/haematol.2019.232793
  • Mahon FX, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–1035. doi:10.1016/S1470-2045(10)70233-3
  • Lee SE, Choi SY, Song HY, et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016;101(6):717–723. doi:10.3324/haematol.2015.139899
  • Campiotti L, Suter MB, Guasti L, et al. Imatinib discontinuation in chronic myeloid leukaemia patients with undetectable BCR-ABL transcript level: a systematic review and a meta-analysis. Eur J Cancer Oxf Engl. 2017;77:48–56.
  • Irani YD, Hughes A, Clarson J, et al. Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells. Br J Haematol. 2020;191(3):433–441. doi:10.1111/bjh.16718
  • Ilander M, Olsson-Strömberg U, Schlums H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31(5):1108–1116. doi:10.1038/leu.2016.360
  • Radich JP, Hochhaus A, Masszi T, et al. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial. Leukemia. 2021;35(5):1344–1355. doi:10.1038/s41375-021-01205-5
  • Diral E, Mori S, Antolini L, et al. Increased tumor burden in patients with chronic myeloid leukemia after 36 months of imatinib discontinuation. Blood. 2020;136(19):2237–2240. doi:10.1182/blood.2019004371
  • Kimura S, Imagawa J, Murai K, et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2020;7(3):e218–25. doi:10.1016/S2352-3026(19)30235-2
  • Fava C, Rege-Cambrin G, Dogliotti I, et al. Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice. Haematologica. 2019;104(8):1589–1596. doi:10.3324/haematol.2018.205054
  • Pagnano KB, Seguro FS, Miranda EC, et al. Duration of major molecular response and discontinuation in deep molecular response (MR4.5) were associated with longer treatment-free survival after imatinib discontinuation - results from two prospective Brazilian trials. Blood. 2019;134:1655. doi:10.1182/blood-2019-125368
  • Shah NP, García-Gutiérrez V, Jiménez-Velasco A, et al. Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study. Leuk Lymphoma. 2020;61(3):650–659. doi:10.1080/10428194.2019.1675879
  • Nagafuji K, Matsumura I, Shimose T, et al. Cessation of nilotinib in patients with chronic myelogenous leukemia who have maintained deep molecular responses for 2 years: a multicenter phase 2 trial, stop nilotinib (NILSt). Int J Hematol. 2019;110(6):675–682. doi:10.1007/s12185-019-02736-5
  • Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747–757. doi:10.1016/S1470-2045(18)30192-X
  • Takahashi N, Tauchi T, Kitamura K, et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol. 2018;107(2):185–193. doi:10.1007/s12185-017-2334-x
  • Kumagai T, Nakaseko C, Nishiwaki K, et al. Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation. Cancer Sci. 2018;109(1):182–192. doi:10.1111/cas.13430
  • Takahashi N, Nishiwaki K, Nakaseko C, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018;103(11):1835–1842. doi:10.3324/haematol.2018.194894
  • Fujisawa S, Ueda Y, Usuki K, et al. Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial). Int J Clin Oncol. 2019;24(4):445–453. doi:10.1007/s10147-018-1368-2
  • Hernández-Boluda JC, Pereira A, Pastor-Galán I, et al. Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients. Blood Cancer J. 2018;8(10):91. doi:10.1038/s41408-018-0125-0
  • Mahon FX, Boquimpani C, Kim DW, et al. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study. Ann Intern Med. 2018;168(7):461–470. doi:10.7326/M17-1094
  • Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–1531. doi:10.1038/leu.2017.63
  • Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846–854. doi:10.1182/blood-2016-09-742205
  • Kim DDH, Bence-Bruckler I, Forrest DL, et al. Treatment-Free Remission Accomplished By Dasatinib (TRAD): preliminary results of the pan-Canadian tyrosine kinase inhibitor discontinuation trial. Blood. 2016;128(22):1922. doi:10.1182/blood.V128.22.1922.1922
  • Imagawa J, Tanaka H, Okada M, et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2(12):e528–535. doi:10.1016/S2352-3026(15)00196-9
  • Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–522. doi:10.1182/blood-2013-02-483750
  • Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol off J Am Soc Clin Oncol. 2014;32(5):424–430. doi:10.1200/JCO.2012.48.5797
  • Thielen N, van der Holt B, Cornelissen JJ, et al. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian cooperative trial for haemato-oncology (HOVON). Eur J Cancer Oxf Engl. 2013;49(15):3242–3246.
  • Mahon FX, Nicolini FE, Noël MP, et al. Preliminary report of the STIM2 study: a multicenter stop imatinib trial for chronic phase chronic myeloid leukemia de novo patients on imatinib. Blood. 2013;122(21):654. doi:10.1182/blood.V122.21.654.654
  • Yhim HY, Lee NR, Song EK, et al. Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response. Leuk Res. 2012;36(6):689–693. doi:10.1016/j.leukres.2012.02.011
  • Matsuki E, Ono Y, Tonegawa K, et al. Detailed Investigation on characteristics of Japanese patients with chronic phase CML who achieved a durable CMR after discontinuation of imatinib – an updated result of the keio STIM study. Blood. 2012;120(21):2788. doi:10.1182/blood.V120.21.2788.2788
  • Vigón L, Luna A, Galán M, et al. Identification of immunological parameters as predictive biomarkers of relapse in patients with chronic myeloid leukemia on treatment-free remission. J Clin Med. 2021;10(1):42. doi:10.3390/jcm10010042
  • Rea D, Henry G, Khaznadar Z, et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica. 2017;102(8):1368–1377. doi:10.3324/haematol.2017.165001
  • Raspadori D, Pacelli P, Sicuranza A, et al. Flow cytometry assessment of CD26+ leukemic stem cells in peripheral blood: a simple and rapid new diagnostic tool for chronic myeloid leukemia. Cytometry B Clin Cytom. 2019;96(4):294–299. doi:10.1002/cyto.b.21764
  • Bocchia M, Sicuranza A, Abruzzese E, et al. Residual peripheral blood CD26+ leukemic stem cells in chronic myeloid leukemia patients during TKI Therapy and during treatment-free remission. Front Oncol. 2018;8:194. doi:10.3389/fonc.2018.00194
  • Stuckey R, López Rodríguez JF, Gómez-Casares MT. Discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia: a review of the biological factors associated with treatment-free remission. Curr Oncol Rep. 2022;24(4):415–426. doi:10.1007/s11912-022-01228-w
  • Cayssials E, Jacomet F, Piccirilli N, et al. Sustained treatment-free remission in chronic myeloid leukaemia is associated with an increased frequency of innate CD8(+) T-cells. Br J Haematol. 2019;186(1):54–59. doi:10.1111/bjh.15858
  • Claudiani S, Apperley JF, Khan A, Khorashad J, Milojkovic D. Prolonged treatment-free remission in chronic myeloid leukemia patients with previous BCR-ABL1 kinase domain mutations. Haematologica. 2020;105(5):e225–7. doi:10.3324/haematol.2019.234179
  • D’Adda M, Farina M, Schieppati F, et al. The e13a2 BCR-ABL transcript negatively affects sustained deep molecular response and the achievement of treatment-free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors. Cancer. 2019;125(10):1674–1682. doi:10.1002/cncr.31977
  • Castagnetti F, Binotto G, Capodanno I, et al. Making Treatment-Free Remission (TFR) easier in chronic myeloid leukemia: fact-checking and practical management tools. Target Oncol. 2021;16(6):823–838. doi:10.1007/s11523-021-00831-4
  • Mori S, Vagge E, le Coutre P, et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015;90(10):910–914. doi:10.1002/ajh.24120
  • Atallah E, Schiffer CA, Radich JP, et al. Assessment of outcomes after stopping tyrosine kinase inhibitors among patients with chronic myeloid leukemia: a nonrandomized clinical trial. JAMA Oncol. 2021;7(1):42–50. doi:10.1001/jamaoncol.2020.5774
  • Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol. 2019;6(7):e375–83. doi:10.1016/S2352-3026(19)30094-8
  • Atallah E, Treatment-Free Remission: SK. the New Goal in CML Therapy. Curr Hematol Malig Rep. 2021;16(5):433–439. doi:10.1007/s11899-021-00653-1
  • Kim DDH, Novitzky-Basso I, Kim TS, et al. Optimal duration of imatinib treatment/deep molecular response for treatment-free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial. Br J Haematol. 2021;193(4):779–791. doi:10.1111/bjh.17447
  • ECOG-ACRIN Cancer Research Group. Phase II study of adding the anti-PD-1 pembrolizumab to tyrosine kinase inhibitors in patients with chronic myeloid leukemia and persistently detectable minimal residual disease; 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT03516279. Accessed February 10, 2023.
  • Katagiri S, Tauchi T, Ando K, Okabe S, Gotoh M, Ohyashiki K. Low body weight and body mass index may be associated with musculoskeletal pain following imatinib discontinuation in chronic myeloid leukemia. Leuk Res Rep. 2017;7:33–35. doi:10.1016/j.lrr.2017.04.002
  • Richter J, Söderlund S, Lübking A, et al. Musculoskeletal Pain in Patients With Chronic Myeloid Leukemia After Discontinuation of Imatinib: a Tyrosine Kinase Inhibitor Withdrawal Syndrome? J Clin Oncol. 2014;32(25):2821–2823. doi:10.1200/JCO.2014.55.6910
  • Flynn KE, Atallah E, Lin L, et al. Patient- and physician-reported pain after tyrosine kinase inhibitor discontinuation among patients with chronic myeloid leukemia. Haematologica. 2022;107(11):2641–2649. doi:10.3324/haematol.2021.280377